The invention relates to the use of selected catechol derivatives as protease inhibitors, and to their use in the treatment of diseases in whose pathogenesis elastase and/or metalloproteases are involved.
Metalloproteases and the serine protease elastase play a central role in the formation and progression of inflammatory diseases in the human body, such as rheumatoid arthritis, periodontitis, the reaction of the skin to UV radiation, as well as primarily non-inflammatory diseases, such as the formation of arteriosclerotic plaques, the mobilisation of tumour cells and the formation of metastases, osteoporosis and arthrosis. The function of the metalloproteases in the course of those processes consists on the one hand in breaking down matrix tissue and on the other hand in activating proinflammatory precursor proteins.
The known protease inhibitors are generally complex molecules which are used for the inhibition of metallo-proteases. They include, in addition to tetracycline derivatives, for the most part the peptidomimetics (Beckett et al., Drug Discovery Today, (1996), p. 16-26). This gives rise to the problem of limited oral availability for the peptidomimetics, since those substances are digested by relatively unspecific peptidases in the gastro-intestinal tract. The compounds of the general formula I are known, for example, from EP-A-0 202 529 and WO 96/31206 as lipoxygenase inhibitors and antihistamines and from WO 82/03729 as adjuvants for the modification of electrodes.
The object of the present invention was to make available compounds which are used as protease inhibitors for the treatment of diseases in whose pathogenesis metallo-proteases and/or elastase are involved.
It has now been found that the requirements made of the compounds were fulfilled by selected catechol derivatives of the general formula I. The compounds are distinguished by pronounced inhibition of metalloprotease and/or elastase activity.
Accordingly, the invention provides selected catechol compounds of the general formula I 
wherein
R1 represents H, aryl-heterocyclyl, C1-16-alkyl, aryl, CHO, CON(CH3)2, COCH3, CO-tert.-butyl, heterocyclyl or C2-16-alkenyl;
R2 represents H, aryl-heterocyclyl, C1-16-alkyl, aryl, CHO, CON(CH3)2, COCH3, CO-tert.-butyl, heterocyclyl or C2-16-alkenyl;
R3 represents H, OH, C2-16-alkoxy or C2-6-alkenyl-COO-C1-6-alkyl;
R4 represents aryl, xe2x80x94CHxe2x95x90CH-aryl, H, unsubstituted and/or OHxe2x80x94, NH2xe2x80x94 or halo-substituted C2-16-mono- or di-alkynyl, heterocyclyl, xe2x80x94C(O)-heterocyclyl, C1-8-alkyl, or R3 and
R4, together with the carbon atoms of the aromatic ring, form a 4- to 6-membered saturated or partially unsaturated cyclic hydrocarbon ring; and
R5 represents aryl, xe2x80x94CHxe2x95x90CH-aryl, H, unsubstituted and/or OHxe2x80x94, NH2xe2x80x94 or halo-substituted C2-16-mono- or di-alkynyl, heterocyclyl, xe2x80x94C(O)-heterocyclyl, C1-8-alkyl, or R4 and R5, together with the carbon atoms of the aromatic ring, form a 4- to 6-membered saturated or partially unsaturated cyclic hydrocarbon ring;
in the form of bases or pharmaceutically acceptable salts, which are used as protease inhibitors in the treatment of diseases in whose pathogenesis elastase and/or metalloproteases are involved.
In the present invention, the expression xe2x80x9cC1-6-alkylxe2x80x9d means straight-chained or branched hydrocarbons having from 1 to 16 carbon atoms. There may be mentioned by way of examples methyl, ethyl, propyl, n-butyl, sec.-butyl, n-pentyl, neopentyl, n-hexyl, n-heptyl, 2,3,4-trimethyl-heptyl, 2,2,3,4,5,5,6-heptamethyl-octyl, n-nonyl, 2,6-diethyl-3,4,5-trimethyl-decanyl, n-undecanyl, n-dodecanyl and 3-ethyl-4-methyl-dodecanyl.
Within the scope of the present invention, the expression xe2x80x9cC1-6-alkoxyxe2x80x9d means straight-chained or branched hydrocarbons having from 1 to 16 carbon atoms, as defined above, which are bonded via the oxygen atom.
The expressions xe2x80x9cC2-6-alkenylxe2x80x9d and xe2x80x9cC2-16-alkenylxe2x80x9d in the present invention mean straight-chained or branched hydrocarbons having from 2 to 6 or from 2 to 16 carbon atoms, respectively, as defined above, which additionally contain a free double bond within the carbon chain.
Within the scope of the present invention, the expression xe2x80x9cC2-16-mono- or di-alkynylxe2x80x9d means straight-chained or branched hydrocarbons having from 2 to 16 carbon atoms, as defined above, which additionally contain one or two free triple bonds within the carbon chain. The hydrocarbon radical may additionally contain substituents from the group OH, NH2 and/or halogen.
The expression xe2x80x9carylxe2x80x9d within the scope of the present invention means phenyls or naphthyls which are unsubstituted or mono- or poly-substituted by OH, F, Cl, CF3, C1-6-alkyl, C1-16-alkoxy, C3-7-cycloalkyl, C2-16-alkenyl, heterocyclyl or by phenyl. The heterocyclyl or phenyl radicals may optionally be condensed on.
Within the scope of the present invention, the expression xe2x80x9cheterocyclylxe2x80x9d means 5- or 6-membered saturated or unsaturated heterocyclic compounds which contain 1 or 2 hetero atoms from the group nitrogen, oxygen and/or sulfur, are optionally provided with a condensed on aryl system, and are unsubstituted or mono- or poly-substituted by OH, F, Cl, CF3, C,1-16-alkyl, C1-6-alkoxy, C2-16-alkenyls, mono- or di-C2-16-alkynyls, C2-16-saturated or unsaturated carboxylic acids or carboxylic acid esters having from 2 to 16 carbon atoms for the hydrocarbon part of the carboxylic acid and from 1 to 6 carbon atoms for the hydrocarbon part in the ester, by heterocyclyl or by phenyl.
Examples of saturated heterocyclyls which may be mentioned are 1,4-dioxane, tetrahydrofuran, pyrrolidine, oxazolidine and 1,4-thioxane.
From the group of the unsaturated heterocyclyls there may be mentioned by way of examples furan, thiophene, pyridine, pyrimidine, pyrazole, thiopyran, pyran, thiazole, oxazole, isoxazole, pyridazine, pyrazine, quinoline, isoquinoline, phthalazine and quinazoline.
Within the scope of the present invention, the term xe2x80x9caryl-heterocyclylxe2x80x9d is to be understood as meaning xe2x80x9carylxe2x80x9d and xe2x80x9cheterocyclylxe2x80x9d as defined above, which are bonded to one another via a single bond.
Preference is given to compounds in which the radicals R1 and R2 represent hydrogen and the radicals R3 to R5 are as defined above.
Preference is given to compounds selected from the group:
5,6,7-trihydroxy-3,4-dihydronaphthalene-2-carboxylic acid methyl ester;
4-nonyloxy-1,2-benzene diol;
(3,4-dihydroxy-phenyl)(5-phenyl-1H-pyrazol-3-yl)-methanone;
4-(2-naphth-2-yl-vinyl)-1,2-benzene diol;
3-(6-hept-1-ynyl-2,3-dihydroxy-phenyl)-acrylic acid methyl ester; and
4-(11-hydroxy-undeca-1,9-diynyl)-1,2-benzene diol.
The compounds of the general formula I according to the invention are used in the treatment of diseases from the group rheumatoid arthritis, periodontitis, arteriosclerotic plaques, osteoporosis, arthrosis, metastasisation and neoangiogenesis of tumours, ulceration of the cornea and reactions of the skin to UV radiation.
The compounds of the general formula I are used especially in the treatment of rheumatoid arthritis, periodontitis, arteriosclerotic plaques, osteoporosis, arthrosis, and metastasisation and neoangiogenesis of tumours.
The catechol derivatives of the general formula I are preferably used in the treatment of osteoporosis, arteriosclerotic plaques and arthrosis.